An in vivo role for B cells in physiological bone turnover has never been reported. Our preliminary investigations into physiological bone turnover in B cell knock out (KO) mice demonstrate that ablation of B cells results in enhanced bone resorption leading to osteopenia. Our preliminary data suggests that the mechanism driving this osteopenia is the result of a bone marrow deficit in Osteoprotegerin (OPG), the physiological decoy receptor of Receptor Activator of NF-kB Ligand (RANKL) and a potent inhibitor of osteoclast formation. Although the major source of bone marrow OPG has generally been considered to be from osteoblasts, our preliminary data suggests that bone marrow B cells represent a considerable and previously unrecognized source of osteoprotegerin in the bone marrow microenvironment and may account for up to half of the total OPG levels in bone. Furthermore we show that mice deficient in CD40 and CD40L, and in T cells likewise suffer a deficit in bone marrow OPG, due to decreased B cell OPG production. This suggests that T cells and B cells are portent protectors of bone mass under basal conditions, through regulation of B cell OPG production. Based on this data we hypothesize that B cell derived OPG is essential for the stabilization of physiological bone mass in vivo and that under basal physiological conditions lymphocytes are critical protectors of bone mass in vivo. The Specific Aims of this R21 application are to provide an unambiguous and definitive demonstration that B cells are critical preservers of physiological bone homeostasis in vivo by virtue of their capacity to secrete copious concentrations of OPG. Specific Aim 1: The generation of a Floxed OPG transgenic mouse, and the production of conditional B cell specific, and Osteoblast specific, OPG null mice. Specific Aim 2: Characterization of the bone phenotypes of a) conditional B cell specific and b) conditional osteoblast specific, OPG KO mice. [unreadable] [unreadable]